1. Field of the Invention
The present invention relates to a pharmaceutical composition or a health functional food composition including an Elsholtziae Herba extract as an active ingredient for the prevention, improvement, or treatment of acute renal failure.
2. Description of the Related Art
Acute renal failure is a clinical syndrome characterized by rapid decline in renal functions, which is caused by a number of factors such as a reduction in renal blood flow, glomerulonephritis, use of nephrotoxic antibiotics and anticancer agents, etc. The acute renal failure is accompanied by reductions in glomerular filtration rate (GFR) and urine output, azotemia caused by retention of nitrogenous waste products, perturbations in fluid and electrolyte balance, etc. Renal impairment in acute renal failure is associated with a high risk of 50% mortality, because it is difficult to restore the functions if the cause is not managed and thus early treatment is failed.
Particularly, azotemia, also called uremia, in acute renal failure is caused by the acute loss of renal function due to damage to renal tubules or reduction in glomerular filtration rate (GFR). A healthy adult must excrete a minimum of about 400 ml of urine each day to eliminate wastes from the body through the kidneys. Urine output less than 400 ml per day may indicate loss of kidney function,
The cause of acute renal failure can be largely divided into three categories on the basis of the kidney: pre-renal acute renal failure caused by inadequate blood circulation to the kidneys, intrinsic acute renal failure caused by damage to the kidney itself, and post-renal acute renal failure caused by an obstruction which can occur at any point of the urinary tract from the renal tubules to urethra. The symptoms of acute renal failure are caused by reduced blood flow to the kidneys, such as profound dehydration, excessive bleeding, burns, severe vomiting, diarrhea, long-term use of diuretics, pancreatitis and peritonitis, sepsis, burns, increased sodium excretion by the kidney, and this status is called pre-renal acute renal failure. In addition, a direct damage to the kidney due to disease or renal toxic substance may cause changes in renal parenchyma, and this status is called intrinsic acute renal failure. Diseases corresponding to intrinsic acute renal failure include glomerulonephritis, renal vasculitis, long-lasting systemic renal failure or drug-induced acute renal tubular necrosis, thrombosis, external injury, atherosclerosis, and tumors in the kidneys.
As described above, there are many factors that cause acute renal failure. However, renal failure is caused by not one factor but complex actions or interactions between different factors. Further, acute renal failure shows a variety of physical signs. In some cases, acute renal failure has no symptom but abnormal findings in laboratory tests. The symptoms involves low urine output, but not in all cases, poor appetite, nausea and vomiting, asterixis, edema, hypertension. In advanced stages, it develops dyspnea, seizures, and coma, leading to death in the most severe case.
The pathophysiology of cisplatin-induced acute renal failure has not been fully understood yet, but it is reported that the mechanisms of anticancer drugs, together with environmental factors, are involved. Exogenous cisplatin-induced acute renal failure that accounts for most of acute renal failure is attributed to absorption of cisplatin by urinary tubular cells in the kidneys.
Recently, it was reported that efficacies of natural substance on acute renal failure can be assessed by measuring changes in ROS (Reactive Oxygen Species), GSH (Glutathione) and p53 (El-Sayed el-SM et al. 2008, Takako Yokozawa, et al 2000). In particular, it is common that levels of ROS, GSH and p53 inducing and worsening symptoms are measured in the severity test of acute renal failure.
Of them, the ROS production level is known as a biochemical index associated with renal injury in various pathological conditions, and ROS-induced DNA damage leads to p53 activation. For this reason, high levels of ROS generally indicate the presence of renal disease. Further, increased GSH content indicates a cell-protecting effect, that is, a defense effect. In cisplatin-induced acute renal failure, the levels of ROS and GSH are changed. This change has been used as a basic index for diagnosing cisplatin-induced acute renal failure.
Meanwhile, it was known that p53 expression levels are increased in cisplatin-induced acute renal failure, and p53 expression is suppressed when therapeutic effects on acute renal failure occur.
Cisplatin (cis-diaminedichloroplatinum II) used to induce acute renal failure is one of anticancer drugs frequently used, and it induces acute renal failure due to structural abnormalities of renal tubules. Free radicals are known to play an important role in cisplatin-induced renal tubule damage. Cisplatin-induced nephrotoxicity is also associated with an increase in lipid peroxidation in the kidney. It was reported that cisplatin itself prevents antioxidant effect in the kidney and reduces the level of GSH showing antioxidant effect in the kidney.
On the other hand, Elsholtziae Herba is prepared from the dried aerial parts of Elsholtzia splendens NAKAI or E. ciliata (THUNB.) HYLANDER, which, is a perennial herb belonging to the family Lamiaceae, and is known to have efficacies of promoting diaphoresis to eliminate summer-heat, promoting diuresis to dissipate dampness, and warming the stomach to regulate the middle, and to be used in oriental medicine for the treatment of feeling cold and chills in summer, headache and fever, chills and anhidrosis, a pain in the midriff, vomiting and diarrhoea, edema, beriberi, etc. (Young-sung Ju. Ungok Herbology (Vol. I). Seoul: Seolimje. 2004. 64-66). Of the prior studies, Korean Patent No. 10-0857691 discloses a composition including the Elsholtziae Herba extract for inhibiting diabetic complications, in which the Elsholtziae Herba extract shows excellent inhibitory effects on advanced glycosylated end products and aldose reductase, so as to be used for the prevention or treatment of diabetic complications. Further, Korean Patent Publication No. 10-2012-0032405 discloses a pharmaceutical composition including the Elsholtziae Herba extract as an active ingredient for the prevention or treatment of allergic diseases, in which the Elsholtziae Herba extract reduces histamine release from mast cells triggered by compound 48/80, generation of allergy-inducing cytokines (TNF-a, IL-4 and IL-8) increased by PMA and A23187, and edema, dermatitis and serum IgE level in an atopic dermatitis mouse model.
However, none of the above documents disclose effects of the Elsholtziae Herba extract on nephrotoxicity, particularly, acute renal failure.
Accordingly, the present inventors have made many efforts to develop a therapeutic agent for acute renal failure, which exhibits fewer side-effects and superior effects as a natural substance. As a result, they found that the Elsholtziae Herba extract exhibits the effects of inhibiting ROS generation, increasing GSH levels, and reducing p53 expression in an acute renal failure cell model and thus it can be used as a composition for the prevention and treatment of acute renal failure, thereby completing the present invention.